Lung cancer is one of the most frequent cancers in the world and remains the most deadly. According to the World Health Organization (WHO), about 12.7 million of new cases of cancers have been diagnosed and among them about 1.6 million of new cases of lung cancer in 2008, which therefore ranks it as the third most frequent cancer. Moreover, lung cancer is the most deadly in the world because about 1.4 million patients died in 2008 from their lung cancer of the about 7.6 million of deaths due to cancer during the same year according to WHO's statistics.
Lung cancer include two main types, i.e., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are named following their cell histology and represent about 15% and about 85% of the primary lung cancers, respectively (Molina et al., Mayo Clin Proc 83:584-594, 2008). SCLC is the most aggressive form and a fast-growing type of lung cancer. Their cells are small and grow quickly to create large tumours. These tumours often metastasize rapidly to other parts of the body like the brain, the bones and the liver. NSCLC is the most common type of lung cancer but it usually grows and metastasizes more slowly than SCLC.
In addition to the above proliferative diseases, the lungs are also a common site for metastasis from different organs such as for metastasis from prostate, breast, colorectal, kidney, head, and neck carcinomas as well as from sarcomas and melanomas (Erhunmwunsee et al., Ann Thorac Surg 88:2052-2060, 2009).
The available treatments of proliferative diseases of the respiratory tract depend on the stage of the disease and typically consist of surgery, radiotherapy, and/or chemotherapy (Molina et al., supra).
Chemotherapeutic agents are currently administrated by oral administration or by intravenous injections, whereby for both administration routes the chemotherapeutic agents are distributed all over the body, i.e., systemically, before reaching the tumour or cancer. Hence, the chemotherapeutic agent inevitably causes severe systemic toxicities to the patient. The lack of selectivity of the chemotherapeutic agents for neoplastic cells such as tumour or cancer cells in comparison with normal cells, will affect rapidly dividing tissues such as bone marrow, gastrointestinal mucosa, skin and gonads to very often induce adverse side effects such as nauseas and vomiting, myelosuppression and alopecia (Parfitt, Martindale 32th edition. Pharmaceutical Press, London, 1999). Severity of the adverse effects can be dose-limiting and can induce an interruption of the treatment, for instance when myelosuppression occurs such as for carboplatin, paclitaxel, docetaxel and vinorelbine. Interruption of the treatment is also the case upon nephrotoxicity such as for cisplatin or neurotoxicity such as for paclitaxel. As the toxicity of the chemotherapeutic agents severely limits the delivered dose, the plasmatic concentrations are often not high enough to be therapeutically efficient at the tumour or cancer site. Moreover, due to the interruption of the treatment to allow normal tissue to recover, tumour or cancer cell repopulation occurs in parallel in various organs (Smyth et al., Informa Healthcare, pp 81-111, 2008). Furthermore, systemic treatment is also associated with multiple adverse events including damaged veins, infection at the catheter introduction site, or air embolisms via the intravenous line (Jain, Methods Mol Biol 437:1-50, 2008).
A therapeutic plateau has been reached today with the different types of treatment and the chemotherapeutics employed for NSCLCs. In fact, the five-year survival rate for NSCLC patients has been about 16% in the United States of America (USA) in the period 1999-2006. This rate is strongly dependent of the stage of the disease with 53%, 24% and 4% for a local, regional or advanced stage, respectively (Howlader et al., SEER Cancer Statistic Review, 1975-2008, 2011).
To increase the selectivity of the chemotherapeutic agent for neoplastic cells and to minimise the exposure of normal cells to the chemotherapeutic agent, exploitation of folate receptor (FR)-mediated drug delivery has been recently proposed. Folate or folic acid is required by eukaryotic cells for nucleotide and DNA synthesis. Therefore, folate receptors and many of the folate-related cell cycle genes are highly expressed in rapidly proliferating cells such as tumour or cancer cells probably as a consequence of their increased requirement for folic acid needed for cell proliferation. FR, especially FR alpha or folate receptor 1 (FOLR1), is overexpressed in many cancers such as ovary, lung, kidney, endometrium, breast, brain, colon, and myeloid cells of hematopoetic lineage (Xia and Low, J Med Chem 53:6811-6824, 2010). When a medication is formulated with a chemotherapeutic agent, folic acid metabolism can be exploited to carry the non-selective chemotherapeutic agent specifically into the FR-expressing neoplastic cells by linking folate to the chemotherapeutic agent. As the chemotherapeutic agent is released after recognition of the folate by the FR and/or internalization by the FR-expressing neoplastic cells, FR-mediated targeting allows avoiding unwanted effects to FR-negative tissues or low FR-expressing tissues (Xia and Low, supra).
For instance, WO 2011/014821 relates to methods of detecting and assessing functionally active folate receptors on tumours and treatment associated with those tumours. WO 2011/014821 also concerns methods and compositions for treating folate receptor expressing epithelial tumours including ovarian, endometrial, or non-small cell lung cancer tumours with a folate-vinca alkaloid conjugate (generally known as “EC145”) in combination with doxorubicin.
The need for further and/or improved formulations for the treatment of proliferative diseases affecting the respiratory tract, such as tumours or cancers affecting the respiratory tract, is self-evident.